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United States Patent |
5,350,752
|
Poss
,   et al.
|
September 27, 1994
|
Dihydropyrimidine derivatives
Abstract
Novel A-II receptor antagonists have the formula
##STR1##
or its isomer
##STR2##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6, are as
defined herein. These compounds inhibit the action of angiotensin II and
are useful, therefore, for example, as antihypertensive agents.
Inventors:
|
Poss; Michael A. (Lawrenceville, NJ);
Lloyd; John (Yardley, PA);
Atwal; Karnail S. (Newtown, PA)
|
Assignee:
|
E. R. Squibb & Sons, Inc. (Princeton, NJ)
|
Appl. No.:
|
812235 |
Filed:
|
December 16, 1991 |
Current U.S. Class: |
514/266.23; 514/81; 514/266.22; 544/231; 544/244; 544/284; 544/287 |
Intern'l Class: |
C07D 239/90; C07D 239/93; C07D 257/09; A61K 037/505 |
Field of Search: |
544/284,287,231,244
514/259
|
References Cited
U.S. Patent Documents
4820843 | Apr., 1989 | Aldrich et al. | 548/252.
|
4855301 | Aug., 1989 | Atwal et al. | 514/269.
|
4870186 | Sep., 1989 | Aldrich et al. | 548/215.
|
4874867 | Oct., 1989 | Aldrich et al. | 548/101.
|
4880804 | Nov., 1989 | Carini et al. | 514/234.
|
5037829 | Aug., 1991 | Freyne et al. | 514/259.
|
5162325 | Nov., 1992 | Chakravarty et al. | 514/259.
|
5162326 | Nov., 1992 | Naka et al. | 514/269.
|
Foreign Patent Documents |
253310 | Jan., 1988 | EP.
| |
323841 | Jul., 1989 | EP.
| |
324377 | Jul., 1989 | EP.
| |
411766 | Feb., 1991 | EP.
| |
0445811A2 | Sep., 1991 | EP.
| |
Other References
Karnail S. Atwal et al., "Substituted 1,4-Dihydropyrimidines, 3, Synthesis
of Selectively Functionalized 2-Hetero-1,4 dihydropyrimidines", J. Org.
Chem., (1989), 54, pp. 5898-5907.
Peter Buhlmayer et al., "Nonpeptidic Angiotensin II Antagonists: Synthesis
and in Vitro Activity of a Series of Novel Naphthalene and
Tetrahydronaphthalene Derivatives", J. Med. Chem., (1991), 34, pp.
3105-3114.
Chiu et al., European Journal of Pharmacology, 157 (1988) pp. 13-21.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Grumbling; Matthew V.
Attorney, Agent or Firm: Park; Ellen K.
Claims
What is claimed is:
1. A compound of the formula I
##STR32##
or its isomer
##STR33##
or a pharmaceutically acceptable salt thereof wherein R.sub.1 is alkyl,
alkenyl or alkynyl or an alkyl, alkenyl or alkynyl group substituted with
F or --CO.sub.2 R.sub.7 ; cycloalkyl; (cycloalkyl)alkyl of 4 to 10 carbon
atoms; (cycloalkyl)alkenyl or (cycloalkyl)alkynyl of 5 to 10 carbon atoms;
--NR.sub.10 R.sub.11 ; --(CH.sub.2).sub.m Z(CH.sub.2).sub.m R.sub.13 ;
benzyl or benzyl substituted with 1 or 2 halogens, alkoxy of 1 to 4 carbon
atoms, alkyl of 1 to 4 carbon atoms, haloalkyl or nitro; --SR.sub.14 ; or
--OR.sub.14 ;
R.sub.2 and R.sub.3 taken together with the carbon atoms to which they are
attached form an aryl group;
R.sub.4 and R.sub.5 are independently selected from hydrogen, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl,
heterocyclo, (heterocyclo)alkyl, haloalkyl or --CO.sub.2 R.sub.7 ;
or R.sub.4 and R.sub.5 taken together with the carbon atom to which they
are attached form a 5- to 7-membered carbocyclic ring which may have
another 5- to 7-membered ring fused thereoto;
or R.sub.4 and R.sub.5 taken together with the carbon atom to which they
are attached form a carbonyl or a thiocarbonyl group;
R.sub.6 is an acid moiety such as hydrogen,
##STR34##
R.sub.7 is hydrogen, alkyl, perfluoroalkyl of 1 to 8 carbon atoms,
cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl
##STR35##
R.sub.8 is hydrogen, alkyl, aryl, arylalkyl or cycloalkyl; R.sub.9 is
alkyl, aryl, alkylaryl, arylalkyl or cycloalkyl;
R.sub.10 and R.sub.11 are independently hydrogen, alkyl of 1 to 6 carbon
atoms, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen
atom to which they are attached form a ring of the formula
##STR36##
R.sub.12 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6
carbon atoms, phenyl or benzyl;
R.sub.13 is hydrogen; alkyl of 1 to 6 carbon atoms; cycloalkyl; alkenyl or
alkynyl of 2 to 4 carbon atoms; or the above alkyl, cycloalkyl, alkenyl or
alkynyl groups optionally substituted with F or --CO.sub.2 R.sub.7 ;
R.sub.14 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl or haloalkyl;
R.sub.18 is hydrogen, alkyl of 1 to 5 carbon atoms or phenyl;
R.sub.19 is --CN, --NO.sub.2 or --CO.sub.2 R.sub.7 ;
Q is --CH.sub.2, --O--, or --NR.sub.8 ;
Z is --O--, --S-- or --NR.sub.12 ;
m is an integer of 1 to 5; and
p is 0, or the integer 1 or 2.
2. A compound of claim 1 wherein
R.sub.1 is n-butyl;
R.sub.2 and R.sub.3 taken together with the carbon atoms to which they are
attached from a fused benzene ring;
R.sub.4 and R.sub.5 together with the carbon atom to which they are
attached form a carbonyl group; and
R.sub.6 is ortho tetrazolyl.
3. A compound of claim 1 having the name
2-Butyl-3-[[5-[2-(2H-tetrazol-5-yl)phenyl]-1-naphthalenyl]methyl]-4(3H)-qu
inazolinone, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound of claim 1 and a
pharmaceutically acceptable carrier.
5. A method for treating hypertension comprising administering to a
mammalian specie in need thereof a therapeutically effective amount of a
composition of claim 4.
6. A method for treating congestive heart failure comprising administering
to a mammalian specie in need thereof a therapeutically effective amount
of a composition of claim 4.
7. A method for preventing cardiac hypertrophy comprising administering to
a mammalian specie in need thereof a therapeutically effective amount of a
composition of claim 4.
Description
FIELD OF THE INVENTION
The present invention relatives to novel dihydropyrimidine derivatives
useful as antihypertensive agents.
SUMMARY OF THE INVENTION
In accordance with the present invention novel compounds, useful for
example as antihypertensive agents, are disclosed. These compounds have
the general formula
##STR3##
and its isomer
##STR4##
and pharmaceutically acceptable salts thereof
wherein R.sub.1 is alkyl, alkenyl or alkynyl or an alkyl, alkenyl or
alkynyl group substituted with F or --CO.sub.2 R.sub.7 ; cycloalkyl;
(cycloalkyl)alkyl of 4 to 10 carbon atoms; (cycloalkyl)alkenyl or
(cycloalkyl)alkynyl of 5 to 10 carbon atoms; --NR.sub.10 R.sub.11 ;
--(CH.sub.2).sub.m Z(CH.sub.2).sub.n R.sub.13 ; benzyl or benzyl
substituted with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of
1 to 4 carbon atoms, haloalkyl or nitro; --SR.sub.14 ; or --OR.sub.14 ;
R.sub.2 is halogen, --CN, --OR.sub.14, --SR.sub.14, --COR.sub.14, R.sub.15,
(R.sub.15 O)alkyl, (R.sub.15 S)alkyl, --CO.sub.2 R.sub.16 or (substituted
amino) alkyl;
R.sub.3 is --CN, --NO.sub.2,
##STR5##
--CONR.sub.10 R.sub.11, (R.sub.14 OCO)alkyl, (R.sub.15 O)alkyl, (R.sub.15
S)alkyl, (R.sub.15 CO)alkyl, --CO.sub.2 R.sub.16, R.sub.17, --COR.sub.17,
--SO.sub.2 R.sub.17 or (R.sub.17 OC)alkyl;
or R.sub.2 and R.sub.3 taken together are
##STR6##
to form a 5- to 7-membered ring with the carbon atoms to which they are
attached;
or R.sub.2 and R.sub.3 taken together with the carbon atoms to which they
are attached form an aryl or heterocyclo group;
R.sub.4 and R.sub.5 are independently selected from hydrogen, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl,
heterocyclo, (heterocyclo)alkyl, haloalkyl or --CO.sub.2 R.sub.7 ;
or R.sub.4 and R.sub.5 taken together with the carbon atom to which they
are attached form a 5- to 7-membered carbocyclic ring which may have
another 5- to 7-membered ring fused thereto;
or R.sub.4 and R.sub.5 together with the carbon atom to which they are
attached form a carbonyl or a thiocarbonyl group;
R.sub.6 is an acid moiety such as hydrogen,
##STR7##
R.sub.7 and R.sub.7 ' are independently hydrogen, alkyl, perfluoroalkyl of
1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl,
##STR8##
R.sub.8 is hydrogen, alkyl, aryl, arylalkyl or cycloalkyl;
R.sub.9 is alkyl, aryl, alkylaryl, arylalkyl or cycloalkyl;
R.sub.10 and R.sub.11 are independently hydrogen, alkyl of 1 to 6 carbon
atoms, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen
atom to which they are attached form a ring of the formula
##STR9##
R.sub.12 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6
carbon atoms, phenyl or benzyl;
R.sub.13 is hydrogen; alkyl of 1 to 6 carbon atoms; cycloalkyl; alkenyl or
alkynyl of 2 to 4 carbon atoms; or the above alkyl, cycloalkyl, alkenyl or
alkynyl groups optionally substituted with F or --CO.sub.2 R.sub.7 ;
R.sub.14 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl or haloalkyl;
R.sub.15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl or haloalkyl;
R.sub.16 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl of 1 to 8
carbon atoms, cycloalkyl, aryl, arylalkyl, (cycloalkyl)alkyl, heterocyclo,
(heterocyclo)alkyl, haloalkyl,
##STR10##
R.sub.17 is aminoalkyl, (substituted amino)alkyl; or R.sub.15 ;
R.sub.18 is hydrogen, alkyl of 1 to 5 carbon atoms or phenyl;
R.sub.19 is --CN, --NO.sub.2 or --CO.sub.2 R.sub.7 ;
Q is --CH.sub.2, --O--, or --NR.sub.8 ;
Z is --O--, --S-- or --NR.sub.12 ;
m is an integer of 1 to 5;
n is an integer of 1 to 5;
p is 0, or the integer 1 or 2; and
q is 0, or the integer 1.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the compounds of formula I and I' and to
pharmaceutical compositions employing such compounds and to methods of
using such compounds. Listed below are definitions of various terms used
to describe the compounds of the instant invention. These definitions
apply to the terms as they are used throughout the specification (unless
they are otherwise limited in specific instances) either individually or
as part of a larger group.
The term "alkyl" refers to both straight and branched chain groups having 1
to 10 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are preferred.
The terms "alkenyl" and "alkynyl" refer to both straight and branched chain
groups. Those groups having 2 to 10 carbon atoms are preferred.
The term "cycloalkyl" refers to groups having 3 to 8 carbon atoms.
The term "alkoxy" refers to groups having 1 to 8 carbon atoms. Alkoxy
groups having 1 to 3 carbon atoms are preferred.
The term "halogen" refers to fluorine, chlorine, bromine and iodine with
fluorine and chlorine being preferred.
The term "haloalkyl" refers to such alkyl groups described above in which
one or more hydrogens have been replaced by chloro, bromo or fluoro groups
such as trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl,
chloromethyl, bromomethyl, etc., trifluoromethyl being preferred.
The term "aryl" refers to phenyl or naphthyl or phenyl or naphthyl
substituted with substituents selected from halogen, alkyl, alkoxy,
carboxy, alkylthio, hydroxy, alkanoyl, nitro, amino, alkylamino,
dialkylamino or trifluoromethyl groups. The aryl group is attached by way
of an available carbon atom or is fused when R.sub.2 and R.sub.3 taken
together with the carbon atoms to which they are attached form the aryl
ring. Preferred aryl groups are phenyl and monosubstituted phenyl and
phenyl is most preferred.
The term "heterocyclo" refers to fully saturated or unsaturated rings of 5
or 6 atoms containing one to four nitrogen atoms, or one oxygen atom, or
one sulfur atom, or one oxygen atom and one or two nitrogen atoms, or one
sulfur atom and one or two nitrogen atoms. The heterocyclo ring is
attached by way of an available carbon atom or is fused when R.sub.2 and
R.sub.3 taken together with the carbon atoms to which they are attached,
form the heterocyclic ring. Preferred monocyclic heterocyclo groups
include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, and
imidazolyl. The heterocycle may also have a substituent selected from
alkyl of 1 to 4 carbons, carboxy, alkoxy of 1 to 4 carbons and alkylthio
of 1 to 4 carbons on an available carbon. The term heterocyclo also
includes bicyclic rings wherein the five or six membered ring containing
oxygen, sulfur and nitrogen atoms as defined above is fused to a benzene
ring and the bicyclic ring is attached by way of an available carbon atom
in the benzene ring. Preferred bicyclic heterocyclo groups include 4, 5, 6
or 7-indolyl, 4, 5, 6 or 7-isoindolyl, 5, 6, 7 or 8-quinolinyl, 5, 6, 7 or
8-isoquinolinyl, 4, 5, 6, or 7-benzothiazolyl, 4, 5, 6 or 7-benzoxazolyl,
4, 5, 6 or 7-benzimidazolyl, 4, 5, 6 or 7-benzoxadiazolyl, and 4, 5, 6 or
7-benzofuranyl. Preferred fused heterocycles include thienyl, furyl,
pyridyl and imidazolyl, optionally substituted as described above.
The term "substituted amino" refers to a group of the formula --NZ.sub.1
Z.sub.2 wherein Z.sub.1 is hydrogen, alkyl, or aryl-(CH.sub.2).sub.p --
and Z.sub.2 is alkyl or aryl--(CH.sub.2).sub.p -- or Z.sub.1 and Z.sub.2
taken together with the nitrogen atom to which they are attached are
1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,
4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl,
4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl,
1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio,
halo, trifluoromethyl or hydroxy.
The compounds of formula I can be prepared by coupling a compound of the
formula
##STR11##
with a compound of the formula
##STR12##
(wherein L is a leaving group, e.g., halogen,
##STR13##
in the presence of a base, such as potassium carbonate, and in an organic
solvent, such as dimethylformamide. The alkylation of compound II with
compound III to give compound I is sometimes accompanied by the isomeric
product I' which can be separated from product I by conventional
chromatographic or crystallization techniques. When R.sub.4 and R.sub.5
are both alkyl groups or taken together they form a spirocarbocylic ring,
I' becomes the exclusive product of alkylation. If R.sub.6 contains any
functional groups (e.g., carboxy, hydroxy, amino groups) that can
interfere with the alkylation of II, then such groups should be protected
during the reaction. Suitable protecting groups include t-butoxycarbonyl,
benzyl, triphenyl methyl, etc.
A preferred method of preparing the compounds of formula I, where R.sub.2
and R.sub.3 together form an aryl group and R.sub.4 and R.sub.5 together
form a carbonyl group, is by reacting compounds of formula II with a
compound of the formula
##STR14##
(wherein L is a leaving group, e.g., halogen,
##STR15##
to provide compounds of formula
##STR16##
which may then be reacted with an azide such as tributyltinazide in an
organic solvent such as xylene to form compounds of formula I where
R.sub.6 is tetrazolyl.
Compounds of formula II wherein R.sub.2 is halogen and R.sub.3 is
--CO.sub.2 R.sub.16 can be prepared by first reacting an amidine of the
formula
##STR17##
(wherein X is halogen) with an olefin of the formula
##STR18##
in an organic solvent, such as dimethylformamide, and in the presence of a
base, such as potassium carbonate, to provide a pyrimidine of the formula
##STR19##
The pyrimidine of formula VI can thereafter be heated in the presence of a
chlorinating agent, e.g., phosphorus oxychloride to provide the
intermediates of formula II were R.sub.2 is chloro and R.sub.3 is
--CO.sub.2 R.sub.16. Compounds of formula II where R.sub.2 is a halogen
other than chloro can be made in a similar fashion.
To provide the intermediates of formula II wherein R.sub.2 is other than
halogen, first the amidine of formula IV can be reacted with an olefin of
the formula
##STR20##
in the presence of a base such as sodium bicarbonate, and in an organic
solvent such as dimethylformamide to provide an intermediate of the
formula
##STR21##
Intermediate VIII can thereafter be cyclized, e.g., by heating in the
presence of an acid, such as p-toluenesulfonic acid, and in an organic
solvent, such as benzene or dimethylformamide, to provide compounds of
formula II where R.sub.2 is other than halogen.
Compounds of formula II, wherein R.sub.4 and R.sub.5 together with the
carbon atom to which they are attached form a carbonyl group, can be
prepared by reacting a compound of the formula
##STR22##
with an amidine of formula IV in the presence of a base such as sodium
bicarbonate or sodium acetate.
Alternatively, compounds of formula II wherein R.sub.4 and R.sub.5 together
form a carbonyl group can be prepared by reacting a compound of the
formula
##STR23##
with an amidine of formula IV in the presence of a base such as sodium
bicarbonate or sodium acetate in a polar solvent such as ethanol or
dimethylformamide.
Preferably, compounds of formula II wherein R.sub.4 and R.sub.5 together
form a carbonyl group and R.sub.2 and R.sub.3 together form a fused aryl
group, can be prepared by reacting anthranilamide with an acyl halide such
as valeryl chloride (R.sub.1 =n-Bu) to form a compound of formula
##STR24##
Compounds of formula Xa are then reacted in an organic solvent such as
toluene with a base such as pyridine in the presence of a dehydrating
agent such as molecular sieves to form the compounds of formula II.
other dihydropyrimidines of formula II can be prepared by methods described
in the literature e.g., K. Atwal et al., J. Org. Chem., Vol. 54, p. 5898
(1989) and references cited therein.
Compounds of formula IIIa can be prepared by reacting a compound of formula
##STR25##
with a halogen (hal) to form compounds of formula
##STR26##
which are then treated with a reducing agent such as lithium aluminum
hydride in an organic solvent such as ether to form compounds of formula
##STR27##
Compounds of formula XIII are then reacted with a chlorinating agent such
as thionyl chloride in an organic solvent such as ether or benzene to form
compounds of formula
##STR28##
which are then reacted with a metal such as zinc in an organic acid such
as acetic acid to form
##STR29##
Compounds of formula XV are then reacted with an alkyllithium such as
butyllithium followed by a zinc salt such as zinc chloride in an organic
solvent such as tetrahydrofuran to give compounds of formula
##STR30##
which are then reacted with an aryl halide such as 2-bromobenzonitrile in
the presence of a catalyst such as tetrakis
(triphenylphosphine)palladium(O) to form compounds of formula
##STR31##
Compounds of formula XVI are then reacted with a halogenating agent such
as N-bromosuccinimide to provide the compounds of formula IIIa.
The compounds of formula I and I' can have an asymmetric center within the
pyrimidine ring as represented by the asterisk (*). Also, any of the R
groups can have an asymmetric center. Thus, the compounds of formula I can
exist in diastereomeric forms or in mixtures thereof. The above-described
processes can utilize racemates, enantiomers or diastereomers as starting
materials. When diastereomeric products are prepared, they can be
separated by conventional chromatographic or fractional crystallization
methods.
When preparing the compounds of the instant invention wherein the
substituent groups contain one or more reactive functionalities such as
hydroxy, amino, tetrazolyl, carboxyl, mercapto or imidazolyl groups, it
may be necessary to protect these groups during the reactions in which
they are used. Suitable protecting groups include benzyloxycarbonyl,
t-butoxycarbonyl, benzyl, benzhydryl, etc. The protecting group is removed
by hydrogenation, treatment with acid, or by other known means following
completion of the reaction.
Preferred compounds of the present invention are those wherein
R.sub.1 is alkyl of 3 to 5 carbons;
R.sub.2 and R.sub.3 taken together with the carbon atoms to which they are
attached form a fused aryl or heterocyclic ring;
R.sub.4 is hydrogen and R.sub.5 is alkyl; or R.sub.4 and R.sub.5 together
with the carbon atom to which they are attached form a carbonyl group; and
R.sub.6 is --CO.sub.2 H or tetrazolyl;
Most preferred compounds of the present invention are those wherein
R.sub.1 is n-butyl;
R.sub.2 and R.sub.3 taken together with the carbon atoms to which they are
attached form a fused benzene ring;
R.sub.4 and R.sub.5 together with the carbon atom to which they are
attached form a carbonyl group; and
R.sub.6 is ortho tetrazolyl;
The present compounds of formula I and I' inhibit the action of the hormone
angiotensin II (A-II) and are therefore useful, for example, as
antihypertensive agents.
The action of the enzyme renin on angiotensinogen, a pseudoglobulin in
blood plasma, produces angiotensin I. Angiotensin I is converted by
angiotensin converting enzyme (ACE) to A-II. The latter is an active
pressor substance which has been implicated as the causative agent in
several forms of hypertension in various mammalian species, e.g., humans.
The compounds of this invention inhibit the action of A-II at its
receptors on target cells and thus prevent the increase in blood pressure
produced by this hormone-receptor interaction. Thus by the administration
of a composition containing one (or a combination) of the compounds of
this invention, angiotensin dependent hypertension in a species of mammal
(e.g., humans) suffering therefrom is alleviated. A single dose, or
preferably two to four divided daily doses, provided on a basis of about
0.1 to 100 mg per kilogram of body weight per day, preferably about 1 to
15 mg per kilogram of body weight per day is appropriate to reduce blood
pressure. The substance is preferably administered orally, but intranasal,
transdermal and parenteral routes such as the subcutaneous, intramuscular,
intravenous or intraperitoneal routes can also employed. The compounds of
this invention are also useful in the treatment/prevention of congestive
heart failure, cardiac hypertrophy, loss of cognitive function, renal
failure and are useful for kidney transplant. In addition, in view of the
role of these compounds in the renin-angiotensin system described above,
the A-II antagonist compounds disclosed herein are also expected to be
useful for the same or similar indications which have developed for ACE
inhibitors.
The compounds of this invention can also be formulated in combination with
a diuretic for the treatment of hypertension or congestive heart failure.
A combination product comprising a compound of this invention and a
diuretic can be administered in an effective amount which comprises a
total daily dosage of about 30 to 600 mg, preferably about 30 to 330 mg of
a compound of this invention, and about 15 to 300 mg, preferably about 15
to 200 mg of the diuretic, to a mammalian species in need thereof.
Exemplary of the diuretics contemplated for use in combination with a
compound of this invention are the thiazide diuretics, e.g.,
chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlothiazide, trichlormethiazide, polythiazide
or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone,
furosemide, musolimine, bumetanide, triamterene, amiloride and
spironolactone and salts of such compounds.
The compounds of formula I and I' can be formulated for use in the
reduction of blood pressure in compositions such as tablets, capsules or
elixirs for oral administration, in sterile solutions or suspensions for
parenteral or intranasal administration, or in transdermal patches. About
10 to 500 mg of a compound of formula I or I' is compounded with a
physiologically acceptable vehicle, carrier, excipient, binder,
preservative, stabilizer, flavor, etc., in a unit dosage form as called
for by accepted pharmaceutical practice. The amount of active substance in
these compositions or preparations is such that a suitable dosage in the
range indicated is obtained.
The following examples and preparations describe the manner and process of
making and using the invention and are illustrative rather than limiting.
It should be understood that there may be other embodiments which fall
within the spirit and scope of the invention as defined by the claims
appended hereto.
EXAMPLE
2-Butyl-3-[[5-[2-(2H-tetrazol-5-yl)phenyl]-1-naphthalenyl]methyl]-4(3H)-qui
nazolinone, monolithium salt
A. 5-Bromo-1-naphthalenecarboxylic acid
Naphthoic acid (20 g, 116 mmol) was suspended in 50 mL of acetic acid and
heated to 100.degree. C. Bromine was added dropwise over 60 minutes and
the reaction became clear before a large amount of yellow solid
precipitated. More acetic acid (50 mL) was added and the reaction was
heated for 90 minutes at 100.degree. C. then allowed to stand at room
temperature overnight. The solid was then collected by filtration, washed
with acetic acid and recrystallized from acetic acid to yield 13.42 g
(46%) of the bromonaphthoic acid. M.p. 252.degree. C.-257.degree. C.
B. 5-Bromo-1-naphthalenemethanol
Lithium aluminum hydride (2.15 g, 56.6 mmol) was suspended in 250 mL of dry
ether at 5.degree. C. and the title A compound (13.38 g, 53.5 mmol) was
added as a solid over 30 minutes. After stirring 30 minutes, the reaction
was quenched with wet ether then dilute sulfuric acid. This mixture was
extracted with a mixture of ethyl acetate and ether and the organic phase
was washed with water, dried over magnesium sulfate and the solvent was
removed to yield 9.38 g (74.5%) of a white solid.
C. 1-Bromo-5-(chloromethyl)naphthalene
The title B compound (9.18 g, 38.9 mmol) was suspended in 92 mL of ether
and 18 mL of benzene. Thionyl chloride (3.9 mL, 53.5 mmol) was added and
the mixture was stirred at room temperature for seven hours. The mixture
was stored at -15.degree. C. for 2.5 days then warmed to room temperature
and additonal thionyl chloride (0.5 mL, 6.9 mmol) was added. The reaction
was stirred for 24 hours at room temperature then filtered and the solvent
removed to provide 8 g of a solid which was adsorbed onto silica gel and
purified by flash chromatography (160 g silica gel;hexane) to yield 4.74 g
(48%) of a white solid.
D. 1-Bromo-5-methylnaphthalene
Powdered zinc (4.24 g, 64.9 mmol) was suspended in ether (20 mL) and acetic
acid (12 mL, 210 mmol) was added. The title C compound (4.48 g, 17.5 mmol)
was dissolved in ether (60 mL) and added dropwise over five minutes. After
stirring for 2.5 hours the reaction was complete (aliquot analyzed by NMR)
and the ether was removed. The residue was partitioned between ethyl
acetate and water and the aqueous layer extracted with ethyl acetate. The
organic phase was dried over magnesium sulfate, filtered and the solvent
removed to provide 3.52 g of a tan solid. Purification by flash
chromatography (140 g silica gel;hexane) yielded 3.11 g (80%) of a white
solid. M.p. 53.degree. C.-56.degree. C.
E. 2-(5-Methyl-1-naphthalenyl)benzonitrile
The title D compound (1.99 g, 9.00 mmol) was dissolved in 10 mL of freshly
distilled tetrahydrofuran, cooled to -78.degree. C. and n-butyllithium
(2.23M in hexane, 4.24 mL, 9.45 mmol) was added dropwise over 10 minutes.
Upon complete addition the reaction was cloudy, bright yellow. After
stirring 40 minutes, zinc chloride (1.0M in ether, 9.45 mL, 9.45 mmol) was
added and the reaction mixture turned to clear pale yellow. The reaction
was stirred 30 minutes, then the cold bath was removed and the reaction
stirred an additional 30 minutes before 2-bromobenzonitrile (1.64 g, 9.45
mmol) and tetrakis(triphenylphosphine)palladium(O) (520 mg, 0.45 mmol)
were added. After stirring 22 hours at 55.degree. C., the reaction mixture
was adsorbed on 10 g of silica gel and purified by flash chromatography
(170 g silica gel; 30% toluene, hexane) to yield 1.31 g (60%) of the
product as a white solid.
F. 2-[5-(Bromomethyl)-1-naphthalenyl]-benzonitrile
The title E compound (1.13 g, 4.64 mmol) was dissolved in 28 mL of 50%
benzene in carbontetrachloride. Azobisisobutyrylnitrile (76 mg, 0.46 mmol)
was added and the mixture was irradiated for 1.5 hours with a 300 w
incandescent light bulb. The solvent was removed and the residue adsorbed
onto 10 g of silica gel and purified by flash chromatography (150 g silica
gel; 10% ethyl acetate, hexane) to yield 1.56 g (100%) of a white solid.
M.p. 147.degree. C.-149.degree. C.
G. 2-Butyl-4(3H)-quinazolinone
1. 2-[(1-Oxopentyl)amino]benzamide
Valeryl chloride (6.0 mL, 50 mmol) was added to a mixture of anthranilamide
(6.8 g, 50 mmol) and triethylamine (7.0 mL, 50 mmol) in tetrahydrofuran
(100 mL) at 25.degree. C. A rapid, exothermic reaction was observed, but
no external cooling was required to prevent reflux. The mixture was
stirred at ambient temperature for 19 hours, after which it was poured
into excess aqueous sodium bicarbonate solution, extracted with ethyl
acetate, dried (magnesium sulfate), and concentrated in vacuo. The residue
was triturated with hexane/ether to give the title compound as a tan solid
(9.9 g, 90%); M.p. 119.degree. C.-120.degree. C.
2. 2-Butyl-4(3H)-quinazolinone
A mixture of the title 1 compound (9.2 g, 42 mmol), toluene (200 mL) and
pyridine (150 mL) was heated to reflux, after which molecular sieves (3
.ANG. 100 mL) were added. The mixture was heated at reflux for two hours,
more molecular sieves (100 mL) were added and reflux was continued for a
total of 18 hours. The mixture was then filtered and the filtrate was
concentrated in vacuo. The residue was dissolved in chloroform (500 mL),
filtered again (millipore), and reconcentrated. The residue was triturated
with hexanes to give the title compound as a white solid (6.8 g, 80%);
M.p. 153.degree. C.-155.degree. C.
H. 2-Butyl-3-[[5-(2-cyanophenyl)
-1-naphthalenyl]methyl]-4(3H)-quinazolinone
The title F compound (500 mg, 1.55 mmol), the title G compound (345 mg,
1.71 mmol) and potassium carbonate (ground, 279 mg, 2.02 mmol) were
dissolved in 3.2 mL of N,N-dimethylformamide. The mixture was stirred for
18 hours then filtered through celite, adsorbed onto 5 g of silica gel and
purified by flash chromatography (100 g silica gel; 20% ethyl acetate,
hexane) to yield 162 mg (23%) of the O-alkylated product and 270 mg (39%)
of the desired product as a white solid. M.p. 92.degree. C.-95.degree. C.;
Anal. calc'd for C.sub.30 H.sub.25 N.sub.3 O.0.24 water: C, 80.46; H, 5.73;
N, 9.38. Found: C, 80.41; H, 5.49; N, 9.43.
I.
2-Butyl-3-[[5-[2-(2H-tetrazol-5-yl)phenyl]-1-naphthalenyl]methyl]-4(3H)-qu
inazolinone, monolithium salt
The title H compound (260 mg, 0.59 mmol) was suspended in 1 mL of xylene.
Tributyltin azide (520 .mu.L) was added and the mixture heated for 20
hours at 100.degree. C. Additional tributyltin azide (200 .mu.L) was added
and the mixture was again heated for 12 hours at 100.degree. C. The
reaction mixture was cooled and purified by flash chromatography (90 g
silica gel; 5% acetic acid, 35% ethyl acetate, hexane) to yield 266 mg of
the desired product as a foamy yellow oil. This oil was dissolved in 1.2
mL of 1.0N lithium hydroxide and purified by column chromatography (100 mL
HP-20; eluting with acetone-water) to yield 211 mg (75%) of the desired
product as the lithium salt. M.p. >270.degree. C.
Anal. calc'd for C.sub.30 H.sub.25 N.sub.6 O.1.70 water: C, 68.88; H, 5.47;
N, 16.06. Found C, 69.23; H, 5.43; N, 15.71.
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